title: Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression.
abstract: The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10mg/kgb.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) and Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits-NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases.
authors.affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India.
authors.forename: Deep Raj
authors.initials: DR
authors.lastname: Sharma
authors.forename: Aditya
authors.initials: A
authors.lastname: Sunkaria
authors.forename: Willayat Yousuf
authors.initials: WY
authors.lastname: Wani
authors.forename: Reeta Kumari
authors.initials: RK
authors.lastname: Sharma
authors.forename: Ramesh J L
authors.initials: RJ
authors.lastname: Kandimalla
authors.forename: Amanjit
authors.initials: A
authors.lastname: Bal
authors.forename: Kiran Dip
authors.initials: KD
authors.lastname: Gill
mesh_terms: D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D063269:Mitochondrial Turnover / Q000187:drug effects / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D014157:Transcription Factors; D000535:Aluminum
keywords: ATP synthase; ATPase; Aluminium; COX; CS; Corpus striatum; Cyt b; Cytochrome b; Cytochrome oxidase; ETC; Electron transport chain; HC; Hippocampus; Mitochondrial biogenesis; Mitochondrial transcription factor A; NADH dehydrogenase; ND; NRF-1; NRF-2; Neurodegeneration; Nuclear respiratory factor-1; Nuclear respiratory factor-2; PGC-1α; Peroxisome proliferator activated receptor gamma co-activator 1a; ROS; Reactive oxygen species; Tfam